Clinical Laboratory Assessment of \u3cem\u3eMycoplasma genitalium\u3c/em\u3e Transcription-Mediated Amplification Using Primary Female Urogenital Specimens

Following analysis of primary cervix, vagina, and first-void female urine specimens for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis via commercial transcription-mediated amplification (TMA), residual material was subjected to Mycoplasma genitalium research-use-only TMA. Representation within a 2,478-specimen retrospective study set was established by comparison to a 6-month audit of clinical C. trachomatis TMA (12,999 specimens) on the basis of the C. trachomatis detection rate, specimen source distribution, clinic location, and age. M. genitalium was detected in 282 (11.4%) patients. This rate was higher than those seen with T. vaginalis (9.0%; P _ 0.005), C. trachomatis (6.2%), and N. gonorrhoeae (1.4%). Positive M. genitalium results were confirmed by repeat testing or alternative-target TMA at a rate of 98.7%. The mean age of the M. genitalium-infected females (24.7 years) was lower than that of the T. vaginalis-infected females (mean, 30.1 years; P\u3c0.0001) and higher than that of the C. trachomatis-infected females (mean, 23.8 years; P_0.003). Of 566 patient encounters positive for at least one sexually transmitted infection (STI), 35.9% exhibited sole detection of M. genitalium (P \u3c 0.0004 versus sole detection of other STI agents) and 26.1% were solely positive for T. vaginalis (P \u3c 0.0002 versus C. trachomatis). The M. genitalium and T. vaginalis detection rates among 755 patients at urban emergency departments were 14.6% and 13.0%, respectively (P _ 0.37). A 10.0% M. genitalium detection rate from other facilities exceeded that of T. vaginalis (7.2%; P _ 0.004). Incorporation of M. genitalium TMA into comprehensive testing programs would detect M. genitalium in a significant proportion of females, particularly those in outpatient obstetrics and gynecology (OB/GYN) settings

Facile FMR1 mRNA structure regulation by interruptions in CGG repeats

RNA metabolism is a major contributor to the pathogenesis of clinical disorders associated with premutation size alleles of the fragile X mental retardation (FMR1) gene. Herein, we determined the structural properties of numerous FMR1 transcripts harboring different numbers of both CGG repeats and AGG interruptions. The stability of hairpins formed by uninterrupted repeat-containing transcripts increased with the lengthening of the repeat tract. Even a single AGG interruption in the repeated sequence dramatically changed the folding of the 5′UTR fragments, typically resulting in branched hairpin structures. Transcripts containing different lengths of CGG repeats, but sharing a common AGG pattern, adopted similar types of secondary structures. We postulate that interruption-dependent structure variants of the FMR1 mRNA contribute to the phenotype diversity, observed in premutation carriers

Social Prescribing: Systematic Review of the Effectiveness of Psychosocial Community Referral Interventions in Primary Care

Introduction: Social prescribing (SP) aims to provide targeted psychosocial support and close the gap between medical and non-medical services. This review assesses the effectiveness of community-based SP interventions. Methods: We performed a systematic review and qualitative synthesis of interventional studies of community referral interventions focused on facilitating psychosocial support. We considered health-related endpoints, other patient reported outcomes, or health care utilization. Six databases, grey literature, and additional trials registers were searched. Results were screened in a two-step process, followed by data extraction, each by two independent reviewers. If data permitted such, effect sizes were calculated. Risk of bias was assessed with the EPHPP and the Cochrane RoB2 tools. Results: We identified 68 reports from 53 different projects, three were controlled studies. Uncontrolled studies with shorter time frames frequently reported positive effects. This could largely not be seen in controlled settings and for longer follow-up periods. Designs, populations, and outcomes evaluated were heterogeneous with high risk of bias for most studies. Discussion and conclusion: Current evidence suggests positive effects of SP on a variety of relevant endpoints. Due to quality deficits in the available studies, scope for conclusions concerning clinical relevance and sustainability is limited. Further methodologically rigorous controlled trials are needed

Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference

The CAG repeat expansions that occur in translated regions of specific genes can cause human genetic disorders known as polyglutamine (poly-Q)-triggered diseases. Huntington’s disease and spinobulbar muscular atrophy (SBMA) are examples of these diseases in which underlying mutations are localized near other trinucleotide repeats in the huntingtin (HTT) and androgen receptor (AR) genes, respectively. Mutant proteins that contain expanded polyglutamine tracts are well-known triggers of pathogenesis in poly-Q diseases, but a toxic role for mutant transcripts has also been proposed. To gain insight into the structural features of complex triplet repeats of HTT and AR transcripts, we determined their structures in vitro and showed the contribution of neighboring repeats to CAG repeat hairpin formation. We also demonstrated that the expanded transcript is retained in the nucleus of human HD fibroblasts and is colocalized with the MBNL1 protein. This suggests that the CAG repeats in the HTT mRNA adopt ds-like RNA conformations in vivo. The intracellular structure of the CAG repeat region of mutant HTT transcripts was not sufficiently stable to be protected from cleavage by an siRNA targeting the repeats and the silencing efficiency was higher for the mutant transcript than for its normal counterpart

CheriRTOS: A Capability Model for Embedded Devices

Embedded systems are deployed ubiquitously among various sectors including automotive, medical, robotics and avionics. As these devices become increasingly connected, the attack surface also increases tremendously; new mechanisms must be deployed to defend against more sophisticated attacks while not violating resource constraints. In this paper we present CheriRTOS on CHERI-64, a hardware-software platform atop Capability Hardware Enhanced RISC Instructions (CHERI) for embedded systems. Our system provides efficient and scalable task isolation, fast and secure inter-task communication, fine-grained memory safety, and real-time guarantees, using hardware capabilities as the sole protection mechanism. We summarize state-of-the-art se- curity and memory safety for embedded systems for comparison with our platform, illustrating the superior substrate provided by CHERI’s capabilities. Finally, our evaluations show that a capability system can be implemented within the constraints of embedded systems

The long-term impact of the MEMA kwa Vijana adolescent sexual and reproductive health intervention: effect of dose and time since intervention exposure.

BACKGROUND: Despite recent decreases in HIV incidence in many sub-Saharan African countries, there is little evidence that specific behavioural interventions have led to a reduction in HIV among young people. Further and wider-scale decreases in HIV require better understanding of when behaviour change occurs and why. The MEMA kwa Vijana adolescent sexual and reproductive health intervention has been implemented in rural Mwanza, Tanzania since 1999. A long-term evaluation in 2007/8 found that the intervention improved knowledge, attitudes to sex and some reported risk behaviours, but not HIV or HSV2 prevalence. The aim of this paper was to assess the differential impact of the intervention according to gender, age, marital status, number of years of exposure and time since last exposure to the intervention. METHODS: In 2007, a cross-sectional survey was conducted in the 20 trial communities among 13,814 young people (15-30 yrs) who had attended intervention or comparison schools between 1999 and 2002. Outcomes for which the intervention had an impact in 2001 or 2007 were included in this subgroup analysis. Data were analysed using cluster-level methods for stratified cluster-randomised trials, using interaction tests to determine if intervention impact differed by subgroup. RESULTS: Taking into account multiplicity of testing, concurrence with a priori hypotheses and consistency within the results no strong effect-modifiers emerged. Impact on pregnancy knowledge and reported attitudes to sex increased with years of exposure to high-quality intervention. CONCLUSIONS: The desirable long-term impact of the MEMA kwa Vijana intervention did not vary greatly according to the subgroups examined. This suggests that the intervention can have an impact on a broad cross-section of young people in rural Mwanza. TRIAL REGISTRATION: ClinicalTrials.gov NCT00248469

The HIV care cascade among female sex workers in Zimbabwe: results of a population-based survey from the Sisters Antiretroviral therapy Programme for Prevention of HIV, an Integrated Response (SAPPH-IRe) Trial.

: Female sex workers (FSW) in sub-Saharan Africa have a higher prevalence of HIV than other women of reproductive age. Social, legal, and structural barriers influence their access to care. Little is known about the HIV diagnosis and care cascade in most countries in Southern Africa. We aimed to describe the HIV diagnosis and care cascade among FSW in Zimbabwe. : We conducted cross-sectional respondent driven sampling (RDS) surveys of FSW in 14 sites across Zimbabwe as the baseline for a cluster-randomised controlled trial investigating a combination HIV prevention and care package. We administered a questionnaire, tested women for HIV and measured viral load. We report the mean, minimum, and maximum respondent-driven sampling-2 weighted site values. : The survey included 2722 women, approximately 200 per site. The mean HIV prevalence was 57.5% (42.8-79.2 site minimum and maximum). Of HIV-positive women, 64.0% (51.6-73.7) were aware of their status, 67.7% (53.4-84.1) of these reported taking antiretroviral therapy, and 77.8% (64.4-90.8) of these had a suppressed HIV viral load (&lt;1000 copies/mL). Among all HIV-positive women, 49.5% had a viral load &lt; 1000 copies/mL. : Although most HIV-positive women aware of their status are accessing antiretroviral therapy, 36.0% of HIV-positive women are unaware of their status and 29.3% of all FSW have an unsuppressed HIV viral load. Investigation and investment into models of testing, treatment, and care are necessary to reach UNAIDS targets for HIV elimination.<br/

Efficient tagged memory

We characterize the cache behavior of an in-memory tag table and demonstrate that an optimized implementation can typically achieve a near-zero memory traffic overhead. Both industry and academia have repeatedly demonstrated tagged memory as a key mechanism to enable enforcement of powerful security invariants, including capabilities pointer integrity, watchpoints, and information-flow tracking. A single-bit tag shadowspace is the most commonly proposed requirement, as one bit is the minimum metadata needed to distinguish between an untyped data word and any number of new hardware-enforced types. We survey various tag shadowspace approaches and identify their common requirements and positive features of their implementations. To avoid non-standard memory widths, we identify the most practical implementation for tag storage to be an in-memory table managed next to the DRAM controller. We characterize the caching performance of such a tag table and demonstrate a DRAM traffic overhead below 5\% for the vast majority of applications. We identify spatial locality on a page scale as the primary factor that enables surprisingly high table cache-ability. We then demonstrate tag-table compression for a set of common applications. A hierarchical structure with elegantly simple optimizations reduces DRAM traffic overhead to below 1\% for most applications. These insights and optimizations pave the way for commercial applications making use of single-bit tags stored in commodity memory